The strategy proposed here for developing novel therapies for treating Alzheimer's disease is based on the finding that neurotoxic and amyloid-depositing fragments apolipoprotein E may play a role in this disease. This, in turn, suggests that degradation of this protein contributes to the pathological changes that occur. If so, a novel approach to treating disease would be the development of means to inhibit the proteolysis of apoE. This Phase I proposal seeks to demonstrate the feasibility of screening protease inhibitors in order to identify compounds that would ultimately lead to the design of novel therapeutic agents to treat AD based on interference with proteolysis of apoE. To this end, the proteolytic activity in human brain homogenates. Initial screening will be based on immunoblotting, which has already been shown to reveal the relevant proteolytic activity. This will be supplemented by optimizing sensitive ELISA assays for eventual high-throughput screening in Phase II. Phase I work will establish the feasibility of this approach by screening an initial list of protease inhibitors obtained from commercial sources.